Advanced paternal age increases the risk of schizophrenia and obsessive–compulsive
disorder in a Chinese Han population
Yuejing Wua,b, Xiang Liua,b, Hongrong Luoa, Wei Denga,b, Gaofeng Zhaoa,b, Qiang Wanga,b, Lan Zhanga,b,
Xiaohong Maa,b, Xiehe Liua, Robin A. Murrayc, David A. Collierd, Tao Lia,b,⁎
aThe Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
bState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
cDepartment of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, UK
dThe MRC SGDP Centre, Institute of Psychiatry, King's College London, London SE5 8AF, UK
a b s t r a c ta r t i c l ei n f o
Received 26 April 2011
Received in revised form 16 January 2012
Accepted 19 January 2012
Using the Structured Clinical Interview for DSM-IV, patient and non-patient version (SCID-P/NP), this study
investigated 351 patients with schizophrenia, 122 with obsessive–compulsive disorder (OCD), and 238
unrelated healthy volunteers in a Chinese Han population. The relative risks posed by advanced paternal
age for schizophrenia and OCD in offspring were computed under logistic regression analyses and adjusted
for the participant's sex, age and co-parent age at birth. Compared to the offspring with paternal age of
25–29 years old, the relative risks rose from 2.660 to 10.183 in the paternal age range of 30–34 and ≥35.
The relative risks for OCD increased from 2.225 to 5.413 in 30–34 and ≥35. For offspring with paternal age of
b25, the odds ratios of developing schizophrenia and OCD were 0.628 and 0.289 respectively, whereas an asso-
ciation between increased maternal age and risk for schizophrenia/OCD was not seen. Interaction analysis
showed an interaction effect between paternal age and maternal age at birth. Such a tendency of risk affected
by parental age for schizophrenia and OCD existed after splitting out the data of early onset patients. Sex-
specific analyses found that the relative risks for schizophrenia with paternal age of 30–34 and ≥35 in male off-
spring were 2.407 and 10.893, and in female offspring were 3.080 and 9.659. The relative risks for OCD with pa-
meanpaternal age of schizophrenia/OCD patients bornbeforethe early 1980s was much greater than that ofpa-
tients who were bornafter then. The findingsillustrated that advanced paternal age is associated with increased
risk for both schizophrenia and OCD in a Chinese Han population, prominently when paternal age is over 35. Bi-
ological and non-biological mechanisms may both be involved in the effects of advanced paternal age on schizo-
phrenia and OCD.
© 2012 Elsevier Ireland Ltd.
Neuropsychiatric disorders like schizophrenia usually are complex
genetic diseases of unknown pathogenesis. There is a paradox that the
worldwide incidence of schizophrenia appears to be largely stable,
though it is highly heritable and confers a substantial reproductive
disadvantage (McGrath et al., 1999; Haukka et al., 2003). Although
schizophrenia is under strong negative genetic selection, its genetic
risk alleles have not been gradually eliminated from the population
(Keller and Miller, 2006; Uher, 2009). For decades, numerous studies
have shown an association between advanced paternal age (APA) and
increased risk for schizophrenia (Johanson 1958; Brown et al., 2002;
Dalman and Allebeck 2002; Byrne et al., 2003; Zammit et al., 2003; El-
Saadi et al., 2004; Sipos et al., 2004; Tsuchiya et al., 2005; Wohl and
Gorwood 2007; Zammit et al., 2008). Furthermore, it was reported
that “sporadic”patients withschizophrenia(i.e.withoutfamilyhistory)
are more likely to have older fathers than the familial patients (i.e. with
family history) (Malaspina et al., 2002). Consequentially, APA is argued
to be a crucial risk factor for schizophrenia.
Although mechanisms underlying the role of APA in adverse health
outcomes in offspring are unclear, it is suggested that accumulated de
novo mutations and/or aberrant epigenetic regulations in spermatogen-
esis with aging are critical (Crow 1999; Malaspina 2001; Perrin et al.,
2007). The biological mechanisms of APA have also been discussed in
studies of other neuropsychiatric
(Reichenberg et al., 2006; Tsuchiya et al., 2008), bipolar disorder (Frans
et al., 2008), and non-psychiatric diseases including nervous system
cancers (Hemminki and Kyyronen, 1999), achondroplasia (Laxova,
1998), Marfan syndrome (Murdoch et al., 1972; Tarin et al., 1998),
Psychiatry Research 198 (2012) 353–359
⁎ Corresponding author at: 28 Dian Xin Nan Road, West China Hospital, Chengdu,
Sichuan, 610041, PR China.
E-mail address: firstname.lastname@example.org (T. Li).
0165-1781© 2012 Elsevier Ireland Ltd.
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/psychres
Open access under CC BY license.
Open access under CC BY license.
Apert syndrome (Glaser et al., 2003; Yoon et al., 2009), and even
intelligence and neurocognitive performance (Malaspina et al., 2005;
Saha et al., 2009).
Along with the biological hypotheses of the adverse role APA plays
in schizophrenia, there is an alternative hypothesis that the selection
of late fatherhood accompanies a predisposition to schizophrenia
(Petersen et al., 2011). Since the early 1980s, great social transitions
have taken place in China, such as urbanization, industrialization and
improvements in education (Cai 2010), as well as attitudes toward
marriage and parenthood (Zhenzhen et al., 2009). We wondered
whetherthetimefor childbearingchanged alongwithsocialtransitions
and implementation of the one-child policy in China, and had an influ-
ence on the susceptibility to certain psychiatric disorders.
Until now, APA has rarely been studied in the anxiety disorders
such as obsessive–compulsive disorder (OCD). Considering the
common neurological soft signs observed in schizophrenia and the
obsessive-compulsive spectrum disorders (Tumkaya et al., 2010),
the high co-morbidity rates for OCD in schizophrenia (Lysaker et
al., 2000; Bottas et al., 2005; Kayahan et al., 2005; Reznik et al.,
2005), and the common pathways (e.g. related to dopaminergic
and serotonic pathways) in schizophrenia and OCD (Tibbo and
Warneke 1999; Azzam and Mathews 2003; Meira-Lima et al., 2004;
Zinkstok et al., 2008), it has been argued that these two diseases
may have some common predisposing factors in neurodevelopment
(Tumkaya et al., 2010) and biological mechanisms.
The previous study of our group has replicated the finding of
association between APA and increased risk for schizophrenia in a
Chinese Han population (Wu et al., 2011). In the present study, we
aimed 1) to investigate whether APA also increases the risk for OCD,
and whether the risks attributable to APA for schizophrenia and OCD
are similar or not, 2) to detect whether the risk from APA for schizo-
phrenia/OCD affects male and female offspringdifferently,and 3) to ex-
plore whether the time of fatherhood and motherhood changed in the
parents of participants along with the social transition.
Thestudywasconductedin theMental Health Center of West ChinaHospital,Sichuan
and OCD were drawn from the inpatient and outpatient units of the Mental Health Center
from January 2003 to December 2006. The patients were enrolled in this analysis if the in-
formation about sex, age and their parents' ages at birth was available. The patients were
Version (SCID-P), which is based on the DSM-IV diagnostic criteria for mental disorders
(First et al., 1997). The patients were excluded from this study if they 1) could not report
either of their parents' ages at the time of their birth or 2) had co-morbid and obsessive–
compulsive symptoms according to SCID-P.
The unrelated healthy controls were enrolled as volunteers who were willing to at-
tend an anonymous survey about their demographic information and receive a current
mental health assessment for free in the psychiatric department of West China Hospi-
tal. The first part of the assessment was a face-to-face interview with a trained psychi-
atrist, and the second part was a cognitive function test if the volunteers were willing
to be evaluated. The exclusion criteria of control participants in the present study were
as follows: 1) those who could not report either of their parents' ages at the time of
their birth, 2) those who were diagnosed to have had psychiatric disorders or were suf-
fering from psychiatric disorders according to the Structured Clinical Interview for
DSM-IV, Non-Patient Version (SCID-NP) (First et al., 1997), and 3) those who had a
family history of psychiatric disorders.
Written informed consent was obtained from each participant. This study was
approved by the Ethics Committee of West China Hospital, Sichuan University.
2.2. Statistical analysis
2.2.1. Demographic features of the participants
To estimate the heterogeneity among the three groups, a chi-square test was used
to compare the sex distribution in the three adult groups by cross-tabulation;
independent-samples t tests were used in the comparisons of participants' current
age, and paternal and maternal age at birth, respectively.
2.2.2. Logistic regression analyses
It is suggested that the 25–29 year old range is the most common reference category
in the majority of previous studies about risk affected by paternal and maternal age for
schizophrenia (Miller et al., 2011). Besides, the mean parental age in the healthy control
group belonged to the 25–29 year old range in the present study. We set the 25–29 year
old category as reference. Due to the small sample size of fathers aged below 20 or over
40 in both the patient groups and the control group, we set the lowest and highest pater-
nal age category at b25 and ≥35 years old. Paternal and maternal ages were divided into
four categories: b25, 25–29, 30–34, and ≥35.
then adjusted for the participant's sex, current age and maternal age at birth accordingly.
The same processes were utilized in the analysis of maternal age at birth as well. An inter-
action analysis for parental age at birth was chosen under the logistic regression model to
explore whether there was an interaction effect between paternal and maternal age at
birth, which could affect the risk for schizophrenia/OCD in offspring.
We stipulated the following: 1) etiological heterogeneity exists in the subtypes of
schizophrenia and OCD with different ages of onset (early onset means having the first
onset at or before 16, and the late onset means having the first onset after 16) (Taylor
2011), 2) APA may have a different impact on the risk for schizophrenia in male and female
offspring (Miller et al., 2011). We stratified the participants by age-of-onset and sex, and re-
2.2.3. Time of parenthood before and after social transition in China
effect of APA for schizophrenia (Petersen et al., 2011), many social environmental factors
are suggested to be essential in the etiology of schizophrenia (Brown 2011), for example,
time trend, migration, and socio-economic status. Great socio-economic changes have
taken place since the early 1980s in China (Cai, 2010). Contrary to the Chinese tradition
of early marriage and large families, many young Chinese couples nowadays not only
postpone marriage and childbearing, but also voluntarily eschew having more children
in response to economic and social pressures, and in accord with their own personal ca-
reer and life goals (Zhenzhen et al., 2009).
In the present study, we took the start of parenthood into account and set a cut-off
of 25 years old in participants, which coincides with the beginning of the period of so-
cial transition in China. We performed comparisons by independent-samples t tests to
explore whether the time for childbearing changed along with the social transition and
varied in groups of schizophrenia patients, OCD patients, and healthy participants.
P-values were considered statistically significant at the α=0.05 level. Statistical
analyses were performed using the SPSS v15.0 software package.
3.1. Demographic features
In total, 351 patients with schizophrenia (167 males, 134 females),
122 patientswithOCD (67males,55females),and238healthycontrols
(122 males, 116 females) were recruited in the present study. There
were 35 patients with schizophrenia and 17 patients with OCD who
had their onset at or before age 16. There were 364 participants who
were born before the early 1980s (187 with schizophrenia, 50 with
phrenia, 72 with OCD and 111 healthy participants). The demographic
characteristics of the three groups are shown in Table 1.
There were no differences in the sex distributions of the three
groups (Pearson χ2=0.780, P=0.677). The current age of patients
with schizophrenia (25.80±7.668) was slightly higher than that of
healthy participants (24.26±5.820) (F=40.668, t′=2.764, P=0.006),
Demographic features of the participants.
Demographic features SchizophreniaOCDControl
MaleFemaleMale Female MaleFemale
Paternal age categories
Paternal age (M±S.D. years)
Maternal age (M±S.D. years)
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359
and there was no difference between the current age of participants
with OCD (23.17±6.984) and that of healthy participants. The paternal
ages inbothparticipantswithschizophrenia andOCDweregreaterthan
those of healthy participants (F=16.275, t′=6.196, Pb0.001, and
F=8.965, t′=4.961, Pb0.001, respectively). The maternal ages of partic-
ipants with schizophrenia/OCD and that of healthy participants did not
differ (See Table 1).
3.2. Logistic regression analyses for risk affected by paternal and maternal
By using logistic regression models, setting the 25–29 category as
reference, and adjusting for the participant's sex, age and maternal
age at birth, the ORs for schizophrenia were 0.628 in b25
(P=0.119, 95% CI: 0.350–1.127), 2.660 in 30–34 (Pb0.001, 95% CI:
1.697–4.169), and 10.183 in ≥35 (Pb0.001, 95% CI: 4.772–21.729).
The ORs for OCD were 0.289 in b25 (P=0.017, 95% CI: 0.105–
0.800), 2.225 in 30–34 (P=0.005, 95% CI: 1.266–3.909), and 5.413
in ≥35 (Pb0.001, 95% CI: 2.154–13.602).
Table 2 shows the ORs for schizophrenia and OCD related to ma-
ternal age as determined by logistic regression analyses. Except for
the OR of mothers in the b25 category for schizophrenia in offspring
(P=0.023, OR=1.635, 95% CI: 1.069–2.500), the ORs for schizophre-
nia and OCD related to maternal age were all non-significant
(P>0.05). Interaction analyses between paternal age and maternal
age at birth were observed both in the group of schizophrenia
(Pb0.001, OR=1.002, 95% CI: 1.001–1.002) and OCD patients
(Pb0.001, OR=1.002, 95% CI: 1.001–1.003).
In short, the risk for schizophrenia/OCD increased when paternal
age rose, whereas the risk of schizophrenia and OCD showed no statis-
tically significant increase in relation to maternal age.
3.3. Specific analyses
In the late onset subgroup, The ORs associated with paternal age for
3.188 in 30–34 (Pb0.001, 95% CI: 1.958–5.188), and 9.828 in ≥35
(Pb0.001, 95% CI: 4.538–21.286) after adjusting for the participant's
sex, current age and maternal age at birth. The ORs effected by paternal
age for OCD were 0.243 in b25 (P=0.028, 95% CI: 0.069–0.860), 2.652
in 30–34 (P=0.002, 95% CI: 1.432–4.914), and 5.320 in ≥35
(P=0.001, 95% CI: 2.067–13.716). As to the early onset subgroup, the
ORs in paternalage categories(b25,30–34, and ≥35) forschizophrenia
and OCD were all non-significant (P>0.05). See Table 2.
The results illustrated that the association of advanced paternal
age with increased risk for schizophrenia/OCD existed even when
we eliminated the data of the early onset participants. The non-
significant ORs calculated in the early onset subgroup may be due
to the relatively small sample (35 in the group of schizophrenia, 17
in the group of OCD).
3.3.2. Sex of offspring
The ORs for schizophrenia in male offspring after adjustment were
0.565 in paternal age of b25 (P=0.200, 95% CI: 0.236–1.353), 5.407 in
30–34 (P=0.004, 95% CI: 1.315–4.407), and 10.893 in ≥35 (Pb0.001,
95% CI: 3.754–31.609). The ORs for OCD in male offspring were 0.202
in paternal age of b25 (P=0.048, 95% CI: 0.041–0.987), 2.629 in
30–34 (P=0.012, 95%CI: 1.242–5.564), and 6.819 in ≥35 (P=0.003,
95% CI: 1.885–24.676). The ORs for schizophrenia in female offspring
after adjustment were 0.695 in paternal age of b25 (P=0.369, 95% CI:
0.315–1.537), 3.082 in 30–34 (P=0.001, 95% CI: 1.566–6.058), and
9.659 in ≥35 (Pb0.001, 95% CI: 3.249–28.715). The OR in paternal age
of ≥35 category for OCD in female offspring was 4.029 (Pb0.039, 95%
CI: 1.069–15.181). See Table 3.
The results indicated that the risk posed by advanced paternal age
for schizophrenia was significantly increased both in male and female
offspring, while the negative effect of advanced paternal age for OCD
in female offspring could not be demonstrated.
3.4. Start of parenthood before and after social transition in China
Table 2 shows the mean parental age at birth, and the compari-
sons between the paternal and maternal age of participants born be-
fore and after the early 1980s in the three groups. The mean paternal
ages of participants born before/after the social transition in both the
group of patients with schizophrenia and the group of patients with
nal age of participants with schizophrenia/OCD who were born before
the social transition was significantly greater than that of participants
with schizophrenia/OCD born after, while there was no difference be-
tween the mean paternal age of healthy participants born before or
after the social transition. Moreover, there was no difference among the
comparisons of the start of motherhood in the three groups before and
after social transition.
The results indicated that although the start of fatherhood was
delayed in fathers of schizophrenia/OCD patients in comparison
with healthy participants, selective delayed fatherhood was not ob-
served in fathers of patients with schizophrenia/OCD who were
born after the early 1980s.
Risk related to paternal/maternal age for schizophrenia/OCD in male/female offspring.
Risk affected by paternal age for
Risk affected by paternal age for
SCZ in male offspring
Risk affected by paternal age for
Risk affected by paternal age for
OCD in male offspring
Risk affected by maternal age for
Risk affected by paternal age for
SCZ in female offspring
Risk affected by maternal age
Parental age categories
Risk affected by paternal age
for OCD in female offspring
Paternal age categories
Abbreviations: SCZ = schizophrenia, OCD = obsessive–compulsive disorder, HC = healthy control.
P, OR, 95% CI were adjusted for participant's sex, present age and co-parental age. There was one patient with schizophrenia who did not have the record of paternal age at birth, and
three patients with schizophrenia and two healthy participants who did not have the record of maternal age at birth.
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359
Although some of the early studies reported inconsistent findings
(Granville-Grossman, 1966), numerous studies have reported the
association between APA and risk for schizophrenia (Johanson
1958; Brown et al., 2002; Dalman and Allebeck 2002; Byrne et al.,
2003; Zammit et al., 2003; El-Saadi et al., 2004; Sipos et al., 2004;
Tsuchiya et al., 2005; Wohl and Gorwood, 2007; Zammit et al.,
2008). The present study found an association between APA and in-
and that the risk for schizophrenia and OCD in offspring both grew in
syncrony with APA. It was found that the later the beginning of father-
hood, the higher the risk of developing schizophrenia/OCD in the off-
spring. We refined the analyses of a previous study about APA and
the risk associated with APA for schizophrenia/OCD existed even after
splitting out the data of early onset participants with schizophrenia/
OCD. There was no association between advanced maternal age at birth
and increased risk for schizophrenia/OCD in offspring.
In the present study, we did not find a significantly different effect
of APA on the risk for male and female offspring to develop schizo-
phrenia/OCD. Previous studies reported inconsistent findings of the
difference between the effect of APA for schizophrenia in male and fe-
male offspring. Byrne et al. (2003) conducted a case–control study
based on a Danish longitudinal register, which recruited 7704 pa-
tients with schizophrenia and 192,590 age- and sex-matched controls
with records of their family socioeconomic and demographic factors
and family history. They found a gender effect that the risk conferred
by advanced paternal age was particularly linked to female offspring
who developed schizophrenia. Sipos et al. (2004) found no difference
in the effect of advanced paternal age in the risk of schizophrenia for
male and female offspring in a population-based cohort study. And in
a meta-analysis, Miller et al. (2011) reported that younger paternal
age (b25) increased the risk for schizophrenia in male offspring but
did not observe selective delayed fatherhood after the early 1980s,
while in the schizophrenia/OCD group, fathers of participants born
after the early 1980s were much younger than those of participants
who were born earlier. We attributed this finding partly to the fathers'
usually having more than one child before the implementation of the
family planning policy since the early 1980s, and partly to the
influences of the social transitions that took place in China not only on
attitudes toward marriage and childbearing. At the same time, there
were also potential confounding risk factors for schizophrenia/OCD,
ic achievement, more stress for parents in the competition at the work-
place, more problems in marriage and child–parent relationships, and
less support for children in a nuclear family than in a large family
formed by three generations (Xu, 2009).
4.1.1. Explanations for the effect of paternal age in the biological aspect
Paternal age has been related to mutation in 1955 (Penrose,
1955). The earliest and classic studies which concerned the associa-
tion between paternal age and schizophrenia (Johanson, 1958;
Malaspina, 2001) explained that biological mechanisms underlie the
risk posed by APA for schizophrenia. De novo mutations (DMNs)
which occur during spermatogenesis as a consequence of fathers'
aging and include de novo point mutation and de novo copy number
variation. It is known that the much higher number of germ cell di-
visions in males, especially older males, results in higher mutation
rate. Human female germ cells undergo 22 mitotic divisions before
they enter the meiotic prophase (Drost and Lee, 1995), and then re-
main in meiotic arrest until adulthood, when ovulation takes place.
In contrast, male germ cells divide continuously, with 23 mitotic
divisions per year after puberty, resulting in 150 divisions by age
20 years and 840 replications by age 50 (Crow, 2000). There is
also more vulnerability to temperature fluctuation in male germ
cell division, and fewer DNA repair mechanisms available, meaning
that male germ cells have more opportunities to accumulate
mutations than females, especially in relation to male age (Risch
et al., 1987).
The increased risk for individuals with older fathers of developing
schizophrenia is also consistent with current hypotheses on the
genetic architecture of complex genetic disorders. The architecture
of schizophrenia is focused on its being composed of a mixture of
both common and rare variants (Wray et al., 2010), although some
propose that schizophrenia is caused exclusively by rare, even fami-
ly-specific mutations which can only be detected by sequencing
(McClellan and King, 2010). Recent empirical studies on the molecular
genetic basis of schizophrenia have identified both common single
Consortium et al., 2009; Stefansson et al., 2009) and rare, largely de
novo, copy number variants (CNVs) (International Schizophrenia
Consortium, 2008; Stefansson et al., 2008; Xu et al., 2008) associated
with the disorder. In addition, rare non-synonymous variants have
been identified in the ABCA13 gene (Knight et al., 2009) and de novo
point mutations in synaptic genes such as SHANK3 (Gauthier et al.,
2010). One current hypothesis is that at least a third of the genetic
risk for schizophrenia derives from common variants of low risk
(Raychaudhuri et al., 2010; Wray et al., 2010), 5–10% from rare CNVs
(Need et al., 2009), and the remaineer being “dark matter” (Manolio
et al.,2009) composed at least in part of rare and intermediate frequen-
cy variants, many of which may be de novo or of recent origin (Uher,
Although it might be expected that mutations are randomly
spread throughout the genome, mutations in specific genes RET,
FGFR2 and FGFR3 are exclusively paternal in origin and increase
sharply with male age (Crow 2000). It has been reported that a
rare structural variant that is associated with schizophrenia, such
as the deletion of 22q11.2, is also related to OCD (Sebat et al.,
2009). The finding of present study raises the issue of the biologi-
cal effects of APA underlying the pathogenesis of schizophrenia
The alternative biological mechanism involves the epigenetic
regulation of the genome, i.e. genomic imprinting (Malaspina,
2001). When imprinted genes inherited from the father are
expressed, those inherited from the mother are silenced, and vice
Independent-samples t tests for the comparisons of paternal age before and after the
Abbreviations: SCZ = schizophrenia, OCD = obsessive–compulsive disorder, HC =
aParticipants who were born before the early 1980s.
bParticipants who were born after the early 1980s.
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359
versa. Genomic methylation is one of the mechanisms for imprinting.
It begins in the male germline in the fetal gonad before birth, and is
completed during postnatal spermatogenesis; it can be erased or re-
established late in spermatogenesis (Zamudio et al., 2008) for pater-
nally imprinted genes. Theprocessofimprintingisvulnerableaspater-
nal age advances. There are already some studies which show that
imprinted genes play a key role in brain development (Keverne et al.,
1996; Isles and Wilkinson, 2000), such as in Turner syndrome (Skuse
et al., 1997), Angelman syndrome (Mann and Bautolomei, 1999), and
autism (Schroer et al., 1998).
Aside from the biological hypotheses to explain the effect of
paternal age for adverse health outcome in offspring, alternative
non-biological hypotheses include the selection of delayed father-
hood which may accompany a predisposition to schizophrenia
(Petersen et al., 2011), the young fathers' lifestyle leading to birth
defects in the offspring (Kazaura et al., 2004), the biological fathers'
non-residence (which can be due to divorce or loss of the father),
poor parenting, and adverse psychopathology for psychological or
psychiatric problems in the offspring (Flouri, 2010). It is suggested
that the quality of father–child interaction is significantly associated
with emotional and behavioral outcomes in both young and older
offspring even after controlling for the quality of mother–child inter-
action, while the mother–child interaction is stronger on emotional
and behavioral outcomes only in young children (Flouri, 2010).
Thus, the social and environmental context of fatherhood, which is
partly related to the father's age at the child's birth and social and
cultural trends, affects susceptibility to schizophrenia/OCD in the
offspring (Brown 2011).
4.2. Strengths and weaknesses
In the present study, we use a “narrow” definition of schizophre-
nia rather than a broader definition of psychosis. Brown et al, (2002)
demonstrated that the strength of the risk conferred by paternal age
according to the diagnoses was higher for schizophrenia than for
other psychoses (Brown et al., 2002). A similar argument was also
seen in other studies (Malaspina, 2001; Zammit et al., 2003). Recent-
ly, in studies of other types of psychosis, such as bipolar disorder, the
paternal age effect is less pronounced (Frans et al., 2008), and has
not been associated with de novo copy number variation (Grozeva
et al., 2010).
Some previous studies concerning the association between APA
and schizophrenia had sensitive designs, such as being based on a
birth register system and well-matched data of economic status of
parents (Byrne et al., 2003), taking into account the family history
of psychiatric disorders or psychosis-like symptoms (Zammit et al.,
2008), and comparing the risk for schizophrenia in offspring with
different birth orders (Petersen et al., 2011). Besides, there are
many other confounding factors associated with schizophrenia,
which have been discussed in former studies. These confounding
factors include parental education, social class at birth (Corcoran et
al., 2009), exposure to early traumatic experiences (Morgan and
Fisher, 2007), like early loss of a parent (Agid et al., 1999), urbanicity
(Pedersen and Mortensen, 2001a), ethnicity (Miller et al., 2011) and
immigration (Cantor-Graae and Selten, 2005; Cooper, 2005), birth
events (Clarke et al., 2006), seasons at birth and latitude in prenatal
periods (McGrath and Welham, 1999; Pedersen and Mortensen,
2001b), etc. In the present case–control study, we could not add
these crucial factors in analyses due to lack of data. Further studies
are needed to confirm current findings of this study and to explore
the genetic and non-genetic risk factors associated with paternal age,
which require collaboration across different disciplines, including epi-
demiology and genome sequencing.
This work was partly funded by National Nature Science
Foundation of China (30530300 and 30125014, TL), the National
Basic Research Program of China (973 Program 2007CB512301,
TL), NARSAD Independent Investigator Award (TL), and the
Wellcome Trust (International Collaborative award to TL, DAC
Agid, O., Shapira, B., Zislin, J., Ritsner, M., Ritsner, M., Hanin, B., Murad, H., Troudart, T.,
Bloch, M., Heresco-Levy, U., Lerer, B., 1999. Environment and vulnerability to major
psychiatric illness: a case control study of early parental loss in major depression,
bipolar disorder and schizophrenia. Molecular Psychiatry 4, 163–172.
Azzam, A., Mathews, C.A., 2003. Meta-analysis of the association between the
catecholamine-O- methyl-transferase gene and obsessive–compulsive disorder.
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: the Official
Publication of the International Society of Psychiatric Genetics 123B, 64–69.
Bottas, A., Cooke,R.G., Richter, M.A., 2005.Comorbidity and pathophysiologyof obsessive–
of schizophrenia? Journal of Psychiatry & Neuroscience 30, 187–193.
Brown, A.S., 2011. The environment and susceptibility to schizophrenia. Progress in
Neurobiology 93, 23–58.
Brown, A.S., Schaefer, C.A., Wyatt, R.J., Begg, M.D., Goetz, R., Bresnahan, M.A., Harkavy-
Friedman, J., Gorman, J.M., Malaspina, D., Susser, E.S., 2002. Paternal age and risk of
schizophrenia in adult offspring. The American Journal of Psychiatry 159, 1528–1533.
Byrne, M., Agerbo, E., Ewald, H., Eaton, W.W., Mortensen, P.B., 2003. Parental age and risk
of schizophrenia: a case–control study. Archives of General Psychiatry 60, 673–678.
Cai, Y., 2010. China's below‐replacement fertility: government policy or socioeconomic
development? Population and Development Review 36, 419–440.
Cantor-Graae, E., Selten, J.P., 2005. Schizophrenia and migration: a meta-analysis and
review. The American Journal of Psychiatry 162, 12–24.
Clarke, M.C., Harley, M., Cannon, M., 2006. The role of obstetric events in schizophrenia.
Schizophrenia Bulletin 32, 3–8.
Cooper, B., 2005. Immigrationandschizophrenia:thesocialcausationhypothesisrevisited.
The British Journal of Psychiatry 186, 361–363.
Corcoran, C., Perrin, M., Harlap, S., Deutsch, L., Fennig, S., Manor, O., Nahon, D., Kimhy, D.,
Malaspina, D., Susser, E., 2009. Effect of socioeconomic status and parents' education
at birth on risk of schizophrenia in offspring. Social Psychiatry and Psychiatric
Epidemiology 44, 265–271.
Crow, J.F., 1999. Spontaneous mutation in man. Mutation Research, Reviews in Mutation
Research 437, 5–9.
Crow, J.F., 2000. The origins, patterns and implications of human spontaneous mutation.
Nature Reviews. Genetics 1, 40–47.
Dalman, C., Allebeck, P., 2002. Paternal age and schizophrenia: further support for an
association. The American Journal of Psychiatry 159, 1591–1592.
germline mutation-rates among Drosophila, mouse, and human. Environmental and
Molecular Mutagenesis 25, 48–64.
El-Saadi, O., Pedersen, C.B., McNeil, T.F., Saha, S., Welham, J., O'Callaghan,E., Cantor-Graae,
E., Chant, D., Mortensen, P.B., McGrath, J., 2004. Paternal and maternal age as risk
factors for psychosis: findings from Denmark, Sweden and Australia. Schizophrenia
Research 67, 227–236.
First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1997. Structured Clinical Interview
for DSM-IV Axis I Disorders: Clinician Version (SCID-CV): Administration Booklet.
American Psychiatric Press, Washington, DC.
Flouri, E., 2010. Fathers' behaviors and children's psychopathology. Clinical Psychology
Review 30, 363–369.
Frans, E.M., Sandin, S., Reichenberg, A., Lichtenstein, P., Langstrom, N., Hultman, C.M.,
2008. Advancing paternal age and bipolar disorder. Archives of General Psychiatry
Gauthier, J., Champagne, N., Lafreniere, R.G., Xiong, L., Spiegelman, D., Brustein, E.,
Lapointe, M., Peng, H.S., Cote, M., Noreau, A., Hamdan, F.F., Addington, A.M.,
Rapoport, J.L., DeLisi, L.E., Krebs, M.O., Joober, R., Fathalli, F., Mouaffak, F.,
Haghighi, A.P., Neri, C., Dube, M.P., Samuels, M.E., Marineau, C., Stone, E.A.,
Awadalla, P., Barker, P.A., Carbonetto, S., Drapeau, P., Rouleau, G.A., S2d Team,
2010. De novo mutations in the gene encoding the synaptic scaffolding protein
SHANK3 in patients ascertained for schizophrenia. Proceedings of the National
Academy of Sciences of the United States of America 107, 7863–7868.
Glaser, R.L., Broman, K.W., Schulman, R.L., Eskenazi, B., Wyrobek, A.J., Jabs, E.W., 2003.
The paternal-age effect in Apert syndrome is due, in part, to the increased frequency
of mutations in sperm. American Journal of Human Genetics 73, 939–947.
Granville-Grossman, K., 1966. Parental age and schizophrenia. The British Journal of
Psychiatry 112, 899–905.
Grozeva, D., Kirov, G., Ivanov, D., Jones, I.R., Jones, L., Green, E.K., St Clair, D.M., Young,
A.H., Ferrier, N., Farmer, A.E., McGuffin, P., Holmans, P.A., Owen, M.J., O'Donovan,
M.C., Craddock, N., Wellcome Trust Case Control Consortium, 2010. Rare copy
number variants: a point of rarity in genetic risk for bipolar disorder and schizo-
phrenia. Archives of General Psychiatry 67, 318–327.
Haukka, J., Suvisaari, J., Lonnqvist, J., 2003. Fertility of patients with schizophrenia, their
siblings, and the general population: a cohort study from 1950 to 1959 in Finland.
The American Journal of Psychiatry 160, 460–463.
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359
Hemminki, K., Kyyronen, P., 1999. Parental age and risk of sporadic and familial cancer
in offspring: implications for germ cell mutagenesis. Epidemiology 10, 747–751.
increase risk of schizophrenia. Nature 455, 237–241.
International Schizophrenia Consortium, Purcell, S.M., Wray, N.R., Stone, J.L., Visscher,
P.M., O'Donovan, M.C., Sullivan, P.F., 2009. Common polygenic variation contributes
to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.
Isles, A.R., Wilkinson, L.S., 2000. Imprinted genes, cognition and behaviour. Trends in
Cognitive Sciences 4, 309–318.
Johanson, E., 1958. A study of schizophrenia in the male: a psychiatric and social study
based on 138 cases with follow up. Acta Psychiatrica et Neurologica Scandinavica
supplementum 125, 1–132.
Kayahan, B., Ozturk, O., Veznedaroglu, B., Eraslan, D., 2005. Obsessive–compulsive
symptoms in schizophrenia: prevalence and clinical correlates. Psychiatry and
Clinical Neurosciences 59, 291–295.
Kazaura, M., Lie, R.T., Skjaerven, R., 2004. Paternal age and the risk of birth defects in
Norway. Annals of Epidemiology 14, 566–570.
Keller, M., Miller, G., 2006. Resolving the evolutionary paradox of common, harmful,
heritable mental disorders. American Journal of Medical Genetics. Part B. Neuro-
psychiatric Genetics 141B, 385–452.
Keverne, E.B., Martel, F.L., Nevison, C.M., 1996. Primate brain evolution: genetic and
functional considerations. Proceedings of the Royal Society B-Biological Sciences
Knight, H.M., Pickard, B.S., Maclean, A., Malloy, M.P., Soares, D.C., McRae, A.F., Condie,
A., White, A., Hawkins, W., McGhee, K., van Beck, M., MacIntyre, D.J., Starr, J.M.,
Deary, I.J., Visscher, P.M., Porteous, D.J., Cannon, R.E., St Clair, D., Muir, W.J.,
Blackwood, D.H., 2009. A cytogenetic abnormality and rare coding variants identify
ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.
American Journal of Human Genetics 85, 833–846.
the centenary of his birth. Genetics 150, 1333–1340.
R.M.,Collier,D.A.,2004.Evidence for association between novel polymorphismsinthe
PRODH gene and schizophrenia in a Chinese population. American Journal of Medical
Genetics. Part B, Neuropsychiatric Genetics 129B, 13–15.
and compulsive symptoms in schizophrenia clinical and neurocognitive correlates.
The Journal of Nervous and Mental Disease 188, 78–83.
Ma, X.H., Wang, Q., Sham, P.C., Liu, X.H., Rabe-Hesketh, S., Sun, X.L., Hu, J.M., Meng, H.Q.,
Chen, W., Chen, E.Y.H., Deng, W., Chan, R.C.K., Murray, R.M., Collier, D.A., Li, T.,
2007. Neurocognitive deficits in first-episode schizophrenic patients and their
first-degree relatives. AmericanJournal of Medical Genetics. PartB,Neuropsychiatric
Genetics 144B, 407–416.
Malaspina, D., 2001. Paternal factors and schizophrenia risk: de novo mutations and
imprinting. Schizophrenia Bulletin 27, 379–393.
Malaspina, D., Corcoran, C., Fahim, C., Berman, A., Harkavy-Friedman, J., Yale, S., Goetz,
D., Goetz, R., Harlap, S., Gorman, J., 2002. Paternal age and sporadic schizophrenia:
evidence for de novo mutations. American Journal of Medical Genetics 114,
Malaspina, D., Reichenberg, A., Weiser, M., Fennig, S., Davidson, M., Harlap, S., Wolitzky,
R., Rabinowitz, J., Susser, E., Knobler, H.Y., 2005. Paternal age and intelligence: im-
plications for age-related genomic changes in male germ cells. Psychiatric Genetics
Mann, M.R.W., Bautolomei, M.S., 1999. Towards a molecular understanding of Prader-
Willi and Angelman syndromes. Human Molecular Genetics 8, 1867–1873.
Manolio, T.A., Collins, F.S., Cox, N.J., Goldstein, D.B., Hindorff, L.A., Hunter, D.J.,
McCarthy, M.I., Ramos, E.M., Cardon, L.R., Chakravarti, A., Cho, J.H., Guttmacher,
A.E., Kong, A., Kruglyak, L., Mardis, E., Rotimi, C.N., Slatkin, M., Valle, D.,
Whittemore, A.S., Boehnke, M., Clark, A.G., Eichler, E.E., Gibson, G., Haines, J.L.,
Mackay, T.F.C., McCarroll, S.A., Visscher, P.M., 2009. Finding the missing heritability
of complex diseases. Nature 461, 747–753.
McClellan, J., King, M.C., 2010. Genomic analysis of mental illness: a changing landscape.
Journal of the American Medical Association 303, 2523–2524.
McGrath, J.J., Welham, J.L., 1999. Season of birth and schizophrenia: a systematic
review and meta-analysis of data from the Southern Hemisphere. Schizophrenia
Research 35, 237–242.
McGrath, J.J., Hearle, J., Jenner, L., Plant, K., Drummond, A., Barkla, J.M., 1999. The fertility
analysis of the catechol-O-methyltransferase (COMT), serotonin transporter (5-HTT)
and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive–compulsive
disorder. Genes, Brain, and Behavior 3, 75–79.
Miller, B., Messias, E., Miettunen, J., Alaraisanen, A., Jarvelin, M.R., Koponen, H.,
Rasanen, P., Isohanni, M., Kirkpatrick, B., 2011. Meta-analysis of paternal age and
schizophrenia risk in male versus female offspring. Schizophrenia Bulletin 37,
Morgan, C., Fisher, H., 2007. Environment and schizophrenia: environmental factors in
schizophrenia:childhoodtrauma — a criticalreview. Schizophrenia Bulletin33, 3–10.
Murdoch, J.L., Walker, B.A., McKusick, V.A., 1972. Parental age effects on the occurrence
of new mutations for the Marfan syndrome. Annals of Human Genetics 35,
Need, A.C., Ge, D.L., Weale, M.E., Maia, J., Feng, S., Heinzen, E.L., Shianna, K.V., Yoon, W.,
Kasperaviciute, D., Gennarelli, M., Strittmatter, W.J., Bonvicini, C., Rossi, G.,
Jayathilake, K., Cola, P.A., McEvoy, J.P., Keefe, R.S.E., Fisher, E.M.C., St Jean, P.L.,
Giegling, I., Hartmann, A.M., Moller, H.J., Ruppert, A., Fraser, G., Crombie, C.,
Middleton, L.T., St Clair, D., Roses, A.D., Muglia, P., Francks, C., Rujescu, D.,
Meltzer, H.Y., Goldstein, D.B., 2009. A genome-wide investigation of SNPs and
CNVs in schizophrenia. PLoS Genetics 5, e1000373.
Pedersen, C.B., Mortensen, P.B., 2001a. Evidence of a dose–response relationship
between urbanicity during upbringing and schizophrenia risk. Archives of General
Psychiatry 58, 1039–1046.
Pedersen, C.B., Mortensen, P.B., 2001b. Family history, place and season of birth as risk
factors for schizophreniainDenmark:a replication andreanalysis.The British Journal
of Psychiatry 179, 46–52.
Penrose, L., 1955. Parental age and mutation. Lancet 269, 312.
Perrin, M.C., Brown, A.S., Malaspina, D., 2007. Aberrant epigenetic regulation could
explain the relationship of paternal age to schizophrenia. Schizophrenia Bulletin
Petersen, L., Mortensen, P.B., Pedersen, C.B., 2011. Paternal age at birth of first child and
risk of schizophrenia. The American Journal of Psychiatry 168, 82–88.
Raychaudhuri, S., Korn, J.M., McCarroll, S.A., Altshuler, D., Sklar, P., Purcell, S., Daly, M.J.,
International Schizophrenia Consortium, 2010. Accurately assessing the risk of
schizophrenia conferred by rare copy-number variation affecting genes with
brain function. PLoS Genetics 6, e1001097.
Reichenberg, A., Gross, R., Weiser, M., Bresnahan, M., Silverman, J., Harlap, S.,
Rabinowitz, J., Shulman, C., Malaspina, D., Lubin, G., Knobler, H.Y., Davidson, M.,
Susser, E., 2006. Advancing paternal age and autism. Archives of General Psychiatry
Reznik, I., Kotler, M., Weizman, A., 2005. Obsessive and compulsive symptoms in
schizophrenia patients — from neuropsychologytoclinicaltypologyandclassification.
The Journal of Neuropsychiatry and Clinical Neurosciences 17, 254–255.
Risch, N., Reich, E.W., Wishnick, M.M., McCarthy, J.G., 1987. Spontaneous mutation and
parental age in humans. American Journal of Human Genetics 41, 218–248.
Saha, S., Barnett, A.G., Foldi, C., Burne, T.H., Eyles, D.W., Buka, S.L., McGrath, J.J., 2009.
Advanced paternal age is associated with impaired neurocognitive outcomes dur-
ing infancy and childhood. PLoS medicine 6, e1000040.
Schroer, R.J., Phelan, M.C., Michaelis, R.C., Crawford, E.C., Skinner, S.A., Cuccaro, M.,
Simensen, R.J., Bishop, J., Skinner, C., Fender, D., Stevenson, R.E., 1998. Autism
and maternally derived aberrations of chromosome 15q. American Journal of Med-
ical Genetics 76, 327–336.
Sebat, J., Levy, D.L., McCarthy, S.E., 2009. Rare structural variants in schizophrenia: one
disorder, multiple mutations; one mutation, multiple disorders. Trends in Genetics
Sipos, A., Rasmussen, F., Harrison, G., Tynelius, P., Lewis, G., Leon, D.A., Gunnell, D.,
2004. Paternal age and schizophrenia: a population based cohort study. British
Medical Journal 329, 1070–1073.
Skuse, D.H., James, R.S., Bishop, D.V.M., Coppin, B., Dalton, P., Aamodt-Leeper, G.,
Bacarese-Hamilton, M., Creswell, C., McGurk, R., Jacobs, P.A., 1997. Evidence from
Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Na-
ture 387, 705–708.
Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal,
R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D.,
Muglia, P., Francks, C., Matthews, P.M., Gylfason, A., Halldorsson, B.V., Gudbjartsson,
D., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Bjornsson, A.,
Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller,
H.J., Hartmann, A., Shianna, K.V., Ge, D.L., Need, A.C., Crombie, C., Fraser, G., Walker,
N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, Tm, Toulopoulou, T.,
Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li,
T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen,
J., Kiemeney, L.A., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir,
U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T.,
Petursson, H., Goldstein, D.B., Nothen, M.M., Peltonen, L., Collier, D.A., St Clair, D.,
Stefansson, K., Group, 2008. Large recurrent microdeletions associated with
schizophrenia. Nature 455, 232–261.
Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D.,
Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson,
O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J.,
Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft,
M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R.,
Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I.,
Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Mason, G., Gulcher,
J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri,
M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A., Melle, I., Djurovic, S.,
Abramova, L., Kaleda, V., Sanjuan, J., de Frutos, R., Bramon, E., Vassos, E., Fraser,
G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon,
J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V.,
Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson,
H., Nothen, M.M., Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair,
D., Goldstein, D.B., Stefansson, K., Collier, D.A., Group, 2009. Common variants
conferring risk of schizophrenia. Nature 460 (7256), 744-U799.
Tarin, J.J., Brines, J., Cano, A., 1998. Long-term effects of delayed parenthood. Human
Reproduction 13, 2371–2376.
Taylor, S., 2011. Early versus late onset obsessive–compulsive disorder: evidence for
distinct subtypes. Clinical Psychology Review 31, 1083–1100.
and biologic overlap. Journal of Psychiatry & Neuroscience 24, 15–24.
N., 2005. Advanced paternal age associated with an elevated risk for schizophrenia in
offspring in a Japanese population. Schizophrenia Research 76, 337–342.
Tsuchiya, K.J., Matsumoto, K., Miyachi, T., Tsujii, M., Nakamura, K., Takagai, S., Kawai,
M., Yagi, A., Iwaki, K., Suda, S., Sugihara, G., Iwata, Y., Matsuzaki, H., Sekine, Y.,
Suzuki, K., Sugiyama, T., Mori, N., Takei, N., 2008. Paternal age at birth and high-
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359
functioning autistic-spectrum disorder in offspring. The British Journal of Psychiatry Download full-text
and obsessive compulsive disorder spectrum. European Psychiatry. doi:10.1016/
Uher, R., 2009. The role of genetic variation in the causation of mental illness: an
evolution-informed framework. Molecular Psychiatry 14, 1072–1082.
Wang, Q., Chan, R., Sun, J.H., Yao, J., Deng, W., Sun, X.L., Liu, X.H., Sham, P.C., Ma, X.H., Meng,
Test is an endophenotypic marker for schizophrenia: a study of first-episode
neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy
population controls. Schizophrenia Research 89, 293–298.
Wohl, M., Gorwood, P., 2007. Paternal ages below or above 35 years old are associated
with a different risk of schizophrenia in the offspring. European Psychiatry 22,
Wray, N.R., Yang, J., Goddard, M.E., Visscher, P.M., 2010. The genetic interpretation of
area under the ROC curve in genomic profiling. PLoS Genetics 6, e1000864.
Wu, Y.J., Liu, X., Zhao, G.F., Ma, X.H., Li, T., 2011. The association between paternal age
and schizophrenia in a Chinese Han population. [Article in Chinese, abstract in
English]. Chinese Journal of Medical Genetics 28, 266–269.
Xu, Q., 2009. Parenting and fatherhood in urban China — a sociological perspective.
China Postgraduate Network Conference 2, 24–36.
Xu, B., Roos, J.L., Levy, S., Van Rensburg, E.J., Gogos, J.A., Karayiorgou, M., 2008. Strong
association of de novo copy number mutations with sporadic schizophrenia.
Nature Genetics 40, 880–885.
Yoon, S.R., Qin, J., Glaser, R.L., Wang Jabs, E., Wexler, N.S., Sokol, R., Arnheim, N.,
Calabrese, P., 2009. The ups and downs of mutation frequencies during aging
can account for the Apert syndrome paternal age effect. PLoS Genetics 5,
Zammit, S., Allebeck, P., Dalman, C., Lundberg, I., Hemmingson, T., Owen, M.J., Lewis, G.,
2003. Paternal age and risk for schizophrenia. The British Journal of Psychiatry 183,
Zammit, S., Horwood, J., Thompson, A., Thomas, K., Menezes, P., Gunnell, D.,
Hollis,C.,Wolke, D., Lewis,G.,
psychosis-like symptoms (PLIKS) are associated with family history of
schizophrenia or paternal age in the ALSPAC birth cohort. Schizophrenia Re-
search 104, 279–286.
Zamudio, N.M., Chong, S.Y., O'Bryan, M.K., 2008. Epigenetic regulation in male germ
cells. Reproduction 136, 131–146.
Zhang, L., Liu, X., Li, T., Yang, Y., Hu, X., Collier, D., 2004. Molecular pharmacogenetic
studies of drug responses to obsessive–compulsive disorder and six functional
genes [article in Chinese, abstract in English]. Chinese Journal of Medical Genetics
Zhenzhen, Z., Cai, Y., Feng, W., Baochang, G., 2009. Below-replacement fertility and
childbearing intention in Jiangsu Province, China. Asian Population Studies 5,
Zinkstok, J., van Nimwegen, L., Van Amelsvoort, T., De Haan, L., Yusuf, M.A., Baas, F.,
Linszen, D., 2008. Catechol-O-methyltransferase gene and obsessive–compulsive
symptoms in patients with recent-onset schizophrenia: preliminary results. Psy-
chiatry Research 157, 1–8.
Harrison,G., 2008. Investigatingif
Y. Wu et al. / Psychiatry Research 198 (2012) 353–359